Publications by authors named "Thomas Fitzgerald"

142 Publications

Young Adult Populations Face Yet Another Barrier to Care With Insurers: Limited Access to Proton Therapy.

Int J Radiat Oncol Biol Phys 2021 Aug;110(5):1505-1507

Department of Radiation Oncology, University of Massachusetts Medical School, Worcester, Massachusetts. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijrobp.2021.03.028DOI Listing
August 2021

Children's Oncology Group Phase III Trial of Reduced-Dose and Reduced-Volume Radiotherapy With Chemotherapy for Newly Diagnosed Average-Risk Medulloblastoma.

J Clin Oncol 2021 Jun 10:JCO2002730. Epub 2021 Jun 10.

Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN.

Purpose: Children with average-risk medulloblastoma (MB) experience survival rates of ≥ 80% at the expense of adverse consequences of treatment. Efforts to mitigate these effects include deintensification of craniospinal irradiation (CSI) dose and volume.

Methods: ACNS0331 (ClinicalTrials.gov identifier: NCT00085735) randomly assigned patients age 3-21 years with average-risk MB to receive posterior fossa radiation therapy (PFRT) or involved field radiation therapy (IFRT) following CSI. Young children (3-7 years) were also randomly assigned to receive standard-dose CSI (SDCSI; 23.4 Gy) or low-dose CSI (LDCSI; 18 Gy). Post hoc molecular classification and mutational analysis contextualized outcomes according to known biologic subgroups (Wingless, Sonic Hedgehog, group 3, and group 4) and genetic biomarkers. Neurocognitive changes and ototoxicity were monitored over time.

Results: Five hundred forty-nine patients were enrolled on study, of which 464 were eligible and evaluable to compare PFRT versus IFRT and 226 for SDCSI versus LDCSI. The five-year event-free survival (EFS) was 82.5% (95% CI, 77.2 to 87.8) and 80.5% (95% CI, 75.2 to 85.8) for the IFRT and PFRT regimens, respectively, and 71.4% (95% CI, 62.8 to 80) and 82.9% (95% CI, 75.6 to 90.2) for the LDCSI and SDCSI regimens, respectively. IFRT was not inferior to PFRT (hazard ratio, 0.97; 94% upper CI, 1.32). LDCSI was inferior to SDCSI (hazard ratio, 1.67%; 80% upper CI, 2.10). Improved EFS was observed in patients with Sonic Hedgehog MB who were randomly assigned to the IFRT arm ( = .018). Patients with group 4 MB receiving LDCSI exhibited inferior EFS ( = .047). Children receiving SDCSI exhibited greater late declines in IQ (estimate = 5.87; = .021).

Conclusion: Reducing the radiation boost volume in average-risk MB is safe and does not compromise survival. Reducing CSI dose in young children with average-risk MB results in inferior outcomes, possibly in a subgroup-dependent manner, but is associated with better neurocognitive outcome. Molecularly informed patient selection warrants further exploration for children with MB to be considered for late-effect sparing approaches.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.20.02730DOI Listing
June 2021

Quality assurance in radiation oncology.

Pediatr Blood Cancer 2021 May;68 Suppl 2:e28609

Radiation Therapy, Prinses Maxima - Center for Pediatric Oncology, Utrecht, The Netherlands.

The Children's Oncology Group (COG) has a strong quality assurance (QA) program managed by the Imaging and Radiation Oncology Core (IROC). This program consists of credentialing centers and providing real-time management of each case for protocol compliant target definition and radiation delivery. In the International Society of Pediatric Oncology (SIOP), the lack of an available, reliable online data platform has been a challenge and the European Society for Paediatric Oncology (SIOPE) quality and excellence in radiotherapy and imaging for children and adolescents with cancer across Europe in clinical trials (QUARTET) program currently provides QA review for prospective clinical trials. The COG and SIOP are fully committed to a QA program that ensures uniform execution of protocol treatments and provides validity of the clinical data used for analysis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.28609DOI Listing
May 2021

Retrospective Inference as a Form of Bounded Rationality, and Its Beneficial Influence on Learning.

Front Artif Intell 2020 18;3. Epub 2020 Feb 18.

The Wellcome Trust Centre for Neuroimaging, University College London, London, United Kingdom.

Probabilistic models of cognition typically assume that agents make inferences about current states by combining new sensory information with fixed beliefs about the past, an approach known as Bayesian filtering. This is computationally parsimonious, but, in general, leads to suboptimal beliefs about past states, since it ignores the fact that new observations typically contain information about the past as well as the present. This is disadvantageous both because knowledge of past states may be intrinsically valuable, and because it impairs learning about fixed or slowly changing parameters of the environment. For these reasons, in offline data analysis it is usual to infer on every set of states using the entire time series of observations, an approach known as (fixed-interval) Bayesian smoothing. Unfortunately, however, this is impractical for real agents, since it requires the maintenance and updating of beliefs about an ever-growing set of states. We propose an intermediate approach, finite retrospective inference (FRI), in which agents perform update beliefs about a limited number of past states (Formally, this represents online fixed-lag smoothing with a sliding window). This can be seen as a form of bounded rationality in which agents seek to optimize the accuracy of their beliefs subject to computational and other resource costs. We show through simulation that this approach has the capacity to significantly increase the accuracy of both inference and learning, using a simple variational scheme applied to both randomly generated Hidden Markov models (HMMs), and a specific application of the HMM, in the form of the widely used probabilistic reversal task. Our proposal thus constitutes a theoretical contribution to normative accounts of bounded rationality, which makes testable empirical predictions that can be explored in future work.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/frai.2020.00002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7861256PMC
February 2020

Stereotactic Body Radiotherapy for Palliation of Hematuria Arising From Urothelial Carcinoma of the Kidney in Unfavorable Surgical Candidates.

Am J Clin Oncol 2021 05;44(5):175-180

Departments of Radiation Oncology.

Introduction: Hematuria can be a distressing and debilitating complication of urothelial carcinoma (UC) of the kidney for patients who are not candidates for surgery or ureteroscopic ablation. We retrospectively assessed the efficacy, tolerability, and safety of stereotactic body radiotherapy (SBRT) for controlling gross hematuria in this patient population.

Materials And Methods: Institutional Review Board (IRB)-approved review of the records, laboratory values, pathology, and imaging of 8 consecutive patients treated with SBRT over a 5-year period for uncontrolled gross hematuria caused by UC of the renal pelvis or calyces.

Results: Therapy was delivered in 3 to 5 treatments over 1 to weeks. Individual treatments lasted an average of 17.2 minutes. No patient experienced treatment-related pain, vomiting, or diarrhea. All enjoyed cessation of bleeding within a week of completing therapy. Hematuria recurred in 2 patients in 4 and 22 months. Of the patients who have not re-bled, 3 expired of metastatic disease or co-morbidities, and 3 remain alive up to 6 years posttreatment. Of patients who have survived longer than a year, creatinine has changed by -0.05 to +0.35, and estimated glomerular filtration rate has fallen by an average of 22%. No patient has required dialysis.

Conclusions: SBRT appears to be an effective and well-tolerated means of palliating gross hematuria secondary to UC of the renal pelvis or calyces in patients who are unfavorable candidates for nephrectomy or ureteroscopic ablation. Treatment was associated with a moderate decline in renal function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/COC.0000000000000801DOI Listing
May 2021

Outcomes After Stereotactic Body Radiation Therapy as a Bridging Modality to Liver Transplantation for Hepatocellular Carcinoma.

Adv Radiat Oncol 2021 Jan-Feb;6(1):100559. Epub 2020 Sep 14.

Department of Radiation Oncology, University of Massachusetts Memorial Medical Center, Worcester, Massachusetts.

Purpose: For patients with hepatocellular carcinoma awaiting liver transplantation (LT), stereotactic body radiation therapy (SBRT) has emerged as a bridging treatment to ensure patients maintain priority status and eligibility per Milan criteria. In this study, we aimed to determine the efficacy and safety of SBRT in such situations.

Methods And Materials: A retrospective analysis was conducted of the outcomes of 27 patients treated with SBRT who were listed for LT at 1 institution. Among these, 20 patients with 26 tumors went on to LT and were the focus of this study. Operative reports and postoperative charts were evaluated for potential radiation-related complications. The explant pathology findings were correlated with equivalent dose in 2 Gy fractions and tumor size.

Results: Median pretreatment tumor size was 3.05 cm. Median total dose of radiation was 50 Gy delivered in 5 fractions. Pathologic complete response (pCR) was achieved in 16 tumors (62%). Median interval from end of SBRT to transplant was 287 days. Of the 21 tumors imaged before transplant, 16 or 76% demonstrated a clinical complete response based on modified Response Evaluation Criteria in Solid Tumors criteria. There was no significant correlation between pCR rate and increasing tumor size (odds ratio [OR], 0.95; 95% confidence interval, 0.595-1.53) or pCR rate and equivalent dose in 2 Gy fractions (OR, 1.03; 95% confidence interval, 0.984-1.07.) No patients experienced radiation-related operative or postoperative complications. Of the 27 patients who were listed for transplant, the dropout rate was 22%. Two of the 5 patients with Child-Pugh score 10 died of liver failure.

Conclusions: These data demonstrate that SBRT as a bridging modality is a feasible option, with a pCR rate comparable to that of other bridging modalities and no additional radiation-related operative or postoperative complications. There was no dose dependence nor size dependence for pCR rate, which may indicate that for the tumor sizes in this study, the radiation doses delivered were sufficiently high.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.adro.2020.08.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897771PMC
September 2020

A Review of Immunotherapy for Stage III and Metastatic Non-Small Cell Lung Cancer and the Rationale for the ECOG-ACRIN EA5181 Study.

Oncologist 2021 06 11;26(6):523-532. Epub 2021 Mar 11.

Department of Hematology Oncology, Cleveland Clinic, Cleveland, Ohio, USA.

ECOG-ACRIN EA5181 is a phase III prospective, randomized trial that randomizes patients undergoing chemo/radiation for locally advanced non-small cell lung cancer (LA-NSCLC) to concomitant durvalumab or no additional therapy, with both arms receiving 1 year of consolidative durvalumab. Radiation dose escalation failed to improve overall survival in RTOG 0617. However, conventionally fractionated radiation to 60 Gy with concomitant chemotherapy is associated with a high risk of local failure (38%-46%). It is hoped that concomitant immunotherapy during chemo/radiation can help decrease the risk of local failure, thereby improving overall survival and progression-free survival with acceptable toxicity. In this article, we review conventional chemo/radiation therapy for LA-NSCLC, as well as the quickly evolving world of immunotherapy in the treatment of non-small cell lung cancer and discuss the rationale and study design of EA5181. IMPLICATIONS FOR PRACTICE: This article provides an up-to-date assessment of how immunotherapy is reshaping the landscape of metastatic non-small cell lung cancer (NSCLC) and how the impact of this therapy is now rapidly moving into the treatment of patients with locally advanced NSCLC who are presenting for curative treatment. This article reviews the recent publications of chemo/radiation as well as those combining immunotherapy with chemotherapy and chemo/radiation, and provides a strategy for improving overall survival of patients with locally advanced NSCLC by using concomitant immunotherapy with standard concurrent chemo/radiation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/onco.13725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176975PMC
June 2021

The state of obstetrics and gynecology residency programs' social media presence.

Am J Obstet Gynecol 2021 04 30;224(4):407-408. Epub 2020 Dec 30.

Department of Learning Health Sciences, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor MI 48109; Department of Obstetrics and Gynecology, Stritch School of Medicine, Loyola University Chicago, Chicago, IL. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajog.2020.12.1209DOI Listing
April 2021

Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma in Patients With Child-Pugh B or C Cirrhosis.

Adv Radiat Oncol 2020 Sep-Oct;5(5):889-896. Epub 2020 Apr 9.

University of Massachusetts Medical School, Worcester, Massachusetts.

Purpose: Our purpose was to report outcomes in patients with Child-Pugh B or C (CP B/C) hepatocellular carcinoma (HCC) treated with stereotactic body radiation therapy (SBRT).

Methods And Materials: Patients with HCC suitable for SBRT were prospectively enrolled in the study from 2012 to 2018. Outcomes in patients with CP B/C were analyzed. Cox proportional hazard models were used to compare survival outcomes between baseline CP score and post-SBRT CP score.

Results: Twenty-three patients with CP B/C with a total of 29 HCC tumors were treated with SBRT. Eighty-seven percent of patients were CP B8-C10. Median tumor size was 3.1 cm (range, 1-10 cm). Median dose delivered was 40 Gy in a median of 5 fractions. Eighteen of 23 patients (78.3%) had been previously treated with transarterial chemoembolization. Median follow-up was 14.5 months. Rates of 6- and 12-month local control were 100% and 92.3%, respectively. Six- and 12-month survival rates were 73.9% and 56.5%, respectively. Median survival was 14.5 months overall and 9.2, 22.5, 14.5, and 14.4 months for patients with CP B7, B8, B9, and C10, respectively. No patients exhibited symptoms of classic radiation-induced liver disease. However, 10 patients had CP score progression, with 4 patients (17%) having a ≥2-point increase in CP score by 6 months (or time of censor). There were 7 liver-related deaths, and based on independent review by a hepatologist, 1 of these deaths may have been attributable to SBRT-related liver injury. Fifteen of 23 patients were listed for liver transplant (LT) at the time of SBRT and 9 went on to receive LT with a pathologic complete response rate of 63.6%. Median survival, excluding patients who received LT, was 7.3 months.

Conclusions: SBRT is a reasonable treatment option for carefully selected patients with CP B7-C10. In our small cohort, there was no detectable difference between local control or overall survival and baseline CP score.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.adro.2020.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557134PMC
April 2020

The potential role of the eGFR in differentiating between true and pseudohyperkalaemia.

Ann Clin Biochem 2020 11 26;57(6):444-455. Epub 2020 Oct 26.

Blood Sciences, Epsom and St Helier University Hospitals NHS Trust, London, UK.

Background: Differentiating between true and pseudohyperkalaemia is essential for patient management. The common causes of pseudohyperkalaemia include haemolysis, blood cell dyscrasias and EDTA contamination. One approach to differentiate between them is by checking the renal function, as it is believed that true hyperkalaemia is rare with normal function. This is logical, but there is limited published evidence to support it. The aim of this study was to investigate the potential role of the estimated glomerular filtration rate in differentiating true from pseudohyperkalaemia.

Methods: GP serum potassium results >6.0 mmol/L from 1 January 2017 to 31 December 2017, with a repeat within seven days, were included. Entries were retrospectively classified as true or pseudohyperkalaemia based on the potassium reference change value and reference interval. If the initial sample had a full blood count, it was classified as normal/abnormal to remove blood cell dyscrasias. Different estimated glomerular filtration rate cut-points were used to determine the potential in differentiating true from pseudohyperkalaemia.

Results: A total of 272 patients were included with potassium results >6.0 mmol/L, with 145 classified as pseudohyperkalaemia. At an estimated glomerular filtration rate of 90 ml/min/1.73 m, the negative predictive value was 81% (95% CI: 67-90%); this increased to 86% (95% CI: 66-95%) by removing patients with abnormal full blood counts. When only patients with an initial potassium ≥6.5 mmol/L were included (regardless of full blood count), at an estimated glomerular filtration rate of 90 ml/min/1.73 m, the negative predictive value was 100%. Lower negative predictive values were seen with decreasing estimated glomerular filtration rate cut-points.

Conclusion: Normal renal function was not associated with true hyperkalaemia, making the estimated glomerular filtration rate a useful tool in predicting true from pseudohyperkalaemia, especially for potassium results ≥6.5 mmol/L.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0004563220966858DOI Listing
November 2020

Practice patterns and recommendations for pediatric image-guided radiotherapy: A Children's Oncology Group report.

Pediatr Blood Cancer 2020 10 9;67(10):e28629. Epub 2020 Aug 9.

Department of Radiation Oncology, Northwestern University, Chicago, Illinois.

This report by the Radiation Oncology Discipline of Children's Oncology Group (COG) describes the practice patterns of pediatric image-guided radiotherapy (IGRT) based on a member survey and provides practice recommendations accordingly. The survey comprised of 11 vignettes asking clinicians about their recommended treatment modalities, IGRT preferences, and frequency of in-room verification. Technical questions asked physicists about imaging protocols, dose reduction, setup correction, and adaptive therapy. In this report, the COG Radiation Oncology Discipline provides an IGRT modality/frequency decision tree and the expert guidelines for the practice of ionizing image guidance in pediatric radiotherapy patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.28629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774502PMC
October 2020

Myxoedema Coma Masquerading as Acute Stroke.

Eur J Case Rep Intern Med 2020 22;7(7):001563. Epub 2020 Apr 22.

St Peter's Hospital, Lyne, Chertsey, Surrey, UK.

This report describes the management of a patient with myxoedema coma masquerading as an acute stroke (with or without 'cold sepsis'). Myxoedema coma is an endocrine emergency occurring when physiological adaptations to untreated hypothyroidism are overwhelmed by an acute precipitant. Even promptly treated, it has an associated mortality of up to 50%.

Learning Points: Early recognition of myxoedema coma is essential, however the chance of misdiagnosis remains high.Key management consists of rapid thyroid hormone replacement (intravenous T4 at 300-500 μg over 24 hours, followed by 50-100 μg daily), supportive measures and the concomitant management of triggers such as infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.12890/2020_001563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350959PMC
April 2020

Positron Emission Tomography-Directed Therapy for Patients With Limited-Stage Diffuse Large B-Cell Lymphoma: Results of Intergroup National Clinical Trials Network Study S1001.

J Clin Oncol 2020 09 13;38(26):3003-3011. Epub 2020 Jul 13.

Division of Hematology/Oncology, Wilmot Cancer Institute, University of Rochester, Rochester, NY.

Purpose: Diffuse large B-cell lymphoma (DLBCL) presents as a limited-stage disease in 25% to 30% of patients, with better overall survival (OS) than that for advanced-stage disease but with continuous relapse regardless of treatment approach. The preferred treatment is abbreviated rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and radiation therapy. On the basis of promising results of positron emission tomography (PET)-directed treatment approaches, we designed a National Clinical Trials Network (NCTN) study to improve outcomes and decrease toxicity.

Methods: Patients with nonbulky (< 10 cm) stage I/II untreated DLBCL received 3 cycles of standard R-CHOP therapy and underwent a centrally reviewed interim PET/computed tomography scan (iPET). Those with a negative iPET proceeded with 1 additional cycle of R-CHOP, whereas those with a positive iPET received involved field radiation therapy followed by ibritumomab tiuxetan radioimmunotherapy.

Results: Of 158 patients enrolled, 132 were eligible and 128 underwent iPET, which was positive in 14 (11%) of the patients. With a median follow-up of 4.92 years (range, 1.1-7.7 years), only 6 patients progressed and 3 died as a result of lymphoma. Eleven patients died as a result of nonlymphoma causes at a median age of 80 years. The 5-year progression-free survival estimate was 87% (95% CI, 79% to 92%) and the OS estimate was 89% (95% CI, 82% to 94%), with iPET-positive and iPET-negative patients having similar outcomes.

Conclusion: To our knowledge, S1001 is the largest prospective study in the United States of limited-stage DLBCL in the rituximab era, with the best NCTN results in this disease subset. With PET-directed therapy, 89% of the patients with a negative iPET received R-CHOP × 4, and only 11% had a positive iPET and required radiation, with both groups having excellent outcomes. The trial establishes R-CHOP × 4 alone as the new standard approach to limited-stage disease for the absolute majority of patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.20.00999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479758PMC
September 2020

The Incidence of Node-Positive Non-small-Cell Lung Cancer Undergoing Sublobar Resection and the Role of Radiation in Its Management.

Front Oncol 2020 26;10:417. Epub 2020 May 26.

University of Massachusetts Medical School, Worcester, MA, United States.

To identify the incidence, preoperative risk factors, and prognosis associated with pathologically positive lymph node (pN+) in patients undergoing a sub-lobar resection (SLR). This is a retrospective study using the National Cancer Database (NCDB) from 2004 to 2014 analyzing SLR excluding those with any preoperative chemotherapy and/or radiation, follow-up <3 months, stage IV disease, or >1 tumor nodule. Multivariable modeling (MVA) was used to determine factors associated with overall survival (OS). Propensity score matching (PSM) was used to determine preoperative risk factors for pN+ in patients having at least one node examined to assess radiation's effect on OS in those patients with pN+ and to determine whether SLR was associated with inferior OS as compared to lobectomy for each nodal stage. A total of 40,202 patients underwent SLR, but only 58.3% had one lymph node examined. Then, 2,615 individuals had pN which decreased progressively from 15.1% in 2004 to 8.9% in 2014 (N1, from 6.3 to 3.0%, and N2, from 8.4 to 5.9%). A lower risk of pN+ was noted for squamous cell carcinomas, bronchioloalveolar adenocarcinoma (BAC), adenocarcinomas, and right upper lobe locations. In the pN+ group, OS was worse without chemotherapy or radiation. Radiation was associated with a strong trend for OS in the entire pN+ group ( = 0.0647) which was largely due to the effects on those having N2 disease ( = 0.009) or R1 resections ( = 0.03), but not N1 involvement ( = 0.87). PSM noted that SLR was associated with an inferior OS as compared to lobectomy by nodal stage in the overall patient population and even for those with tumors <2 cm. pN+ incidence in SLRs has decreased over time. SLR was associated with inferior OS as compared to lobectomy by nodal stage. Radiation appears to improve the OS in patients undergoing SLR with pN+, especially in those with N2 nodal involvement and/or positive margins.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2020.00417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264374PMC
May 2020

Treatment Toxicity: Radiation.

Hematol Oncol Clin North Am 2019 12 1;33(6):1027-1039. Epub 2019 Oct 1.

Department of Radiation Oncology, University of Massachusetts Medical School/UMass Memorial Health Care, 55 Lake Avenue North, Worcester, MA 01655, USA.

Intentional and unintentional radiation exposures have a powerful impact on normal tissue function and can induce short-term and long-term injury to all cell systems. Radiation effects can lead to lifetime-defining health issues for a patient and can produce complications to all organ systems. Providers need to understand acute and late effects of radiation treatment and how the fingerprints of therapy can have an impact on health care in later life. This article reviews current knowledge concerning normal tissue tolerance with therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.hoc.2019.08.010DOI Listing
December 2019

Increasing Fat Graft Retention in Irradiated Tissue after Preconditioning with External Volume Expansion.

Plast Reconstr Surg 2020 01;145(1):103-112

Worcester, Mass.; Padova, Italy; Edinburgh, United Kingdom; and Beijing, People's Republic of China.

Background: Fat grafting is an adjuvant that may improve the quality of radiation-damaged tissue. However, fat grafting for volume restoration in irradiated sites may be less effective because of a poorly vascularized fibrotic recipient bed. External volume expansion has emerged as a potential technique to prepare the recipient sites for improved survival of grafted fat. The authors previously demonstrated increased vasculature with external volume expansion stimulation of irradiated tissues. The authors now hypothesize that external volume expansion's improvements in recipient-site vascularity will increase the volume retention and quality of fat grafts in fibrotic irradiated sites.

Methods: Athymic mice were irradiated until development of chronic radiation injury. Then, the irradiated site was stimulated by external volume expansion (external volume expansion group), followed by subcutaneous fat grafting. Grafts in an irradiated site without external volume expansion stimulation (irradiated control group) and grafts in a healthy nonirradiated (nonirradiated control group) site were used as controls. All grafts were monitored for 8 weeks and evaluated both histologically and by micro-computed tomography for analysis of volume retention.

Results: Hyperspectral imaging confirmed a 25 percent decrease in vascularity of irradiated tissue (irradiated control group) compared with nonirradiated tissue (nonirradiated control group). Grafts in the irradiated control group retained 11 percent less volume than grafts in the nonirradiated control group. The experimental external volume expansion group achieved a 20 percent (p = 0.01) increase in retained graft volume compared with the irradiated control group.

Conclusions: External volume expansion stimulation can mitigate the effects of irradiation at the recipient site and in turn help preserve fat graft volume retention. Possible mechanisms include increased vascularity, adipogenic conversion, and increased compliance of a fibrotic recipient site.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PRS.0000000000006372DOI Listing
January 2020

The VEGF receptor neuropilin 2 promotes homologous recombination by stimulating YAP/TAZ-mediated Rad51 expression.

Proc Natl Acad Sci U S A 2019 07 24;116(28):14174-14180. Epub 2019 Jun 24.

Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605;

Vascular endothelial growth factor (VEGF) signaling in tumor cells mediated by neuropilins (NRPs) contributes to the aggressive nature of several cancers, including triple-negative breast cancer (TNBC), independently of its role in angiogenesis. Understanding the mechanisms by which VEGF-NRP signaling contributes to the phenotype of such cancers is a significant and timely problem. We report that VEGF-NRP2 promote homologous recombination (HR) in BRCA1 wild-type TNBC cells by contributing to the expression and function of Rad51, an essential enzyme in the HR pathway that mediates efficient DNA double-strand break repair. Mechanistically, we provide evidence that VEGF-NRP2 stimulates YAP/TAZ-dependent Rad51 expression and that Rad51 is a direct YAP/TAZ-TEAD transcriptional target. We also discovered that VEGF-NRP2-YAP/TAZ signaling contributes to the resistance of TNBC cells to cisplatin and that Rad51 rescues the defects in DNA repair upon inhibition of either VEGF-NRP2 or YAP/TAZ. These findings reveal roles for VEGF-NRP2 and YAP/TAZ in DNA repair, and they indicate a unified mechanism involving VEGF-NRP2, YAP/TAZ, and Rad51 that contributes to resistance to platinum chemotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1821194116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628806PMC
July 2019

Modeling subjective belief states in computational psychiatry: interoceptive inference as a candidate framework.

Psychopharmacology (Berl) 2019 Aug 22;236(8):2405-2412. Epub 2019 Jun 22.

Wellcome Centre for Human Neuroimaging, University College London, London, England.

The nascent field computational psychiatry has undergone exponential growth since its inception. To date, much of the published work has focused on choice behaviors, which are primarily modeled within a reinforcement learning framework. While this initial normative effort represents a milestone in psychiatry research, the reality is that many psychiatric disorders are defined by disturbances in subjective states (e.g., depression, anxiety) and associated beliefs (e.g., dysmorphophobia, paranoid ideation), which are not considered in normative models. In this paper, we present interoceptive inference as a candidate framework for modeling subjective-and associated belief-states in computational psychiatry. We first introduce the notion and significance of modeling subjective states in computational psychiatry. Next, we present the interoceptive inference framework, and in particular focus on the relationship between interoceptive inference (i.e., belief updating) and emotions. Lastly, we will use drug craving as an example of subjective states to demonstrate the feasibility of using interoceptive inference to model the psychopathology of subjective states.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00213-019-05300-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697568PMC
August 2019

Computational mechanisms of curiosity and goal-directed exploration.

Elife 2019 05 10;8. Epub 2019 May 10.

Wellcome Centre for Human Neuroimaging, University College London, London, United Kingdom.

Successful behaviour depends on the right balance between maximising reward and soliciting information about the world. Here, we show how different types of information-gain emerge when casting behaviour as surprise minimisation. We present two distinct mechanisms for goal-directed exploration that express separable profiles of active sampling to reduce uncertainty. 'Hidden state' exploration motivates agents to sample unambiguous observations to accurately infer the (hidden) state of the world. Conversely, 'model parameter' exploration, compels agents to sample outcomes associated with high uncertainty, if they are informative for their representation of the task structure. We illustrate the emergence of these types of information-gain, termed active inference and active learning, and show how these forms of exploration induce distinct patterns of 'Bayes-optimal' behaviour. Our findings provide a computational framework for understanding how distinct levels of uncertainty systematically affect the exploration-exploitation trade-off in decision-making.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.41703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6510535PMC
May 2019

An quality assurance study of contouring target volumes in thoracic tumors within a cooperative group setting.

Clin Transl Radiat Oncol 2019 Feb 6;15:83-92. Epub 2019 Jan 6.

Department of Radiation Oncology, University of Texas M.D. Anderson Cancer Center, TX 77030, USA.

Introduction: Target delineation variability is a significant technical impediment in multi-institutional trials which employ intensity modulated radiotherapy (IMRT), as there is a real potential for clinically meaningful variances that can impact the outcomes in clinical trials. The goal of this study is to determine the variability of target delineation among participants from different institutions as part of Southwest Oncology Group (SWOG) Radiotherapy Committee's multi-institutional quality assurance study in patients with Pancoast tumors as a "dry run" for trial implementation.

Methods: CT simulation scans were acquired from four patients with Pancoast tumor. Two patients had simulation 4D-CT and FDG-FDG PET-CT while two patients had 3D-CT and FDG-FDG PET-CT. Seventeen SWOG-affiliated physicians independently delineated target volumes defined as gross primary and nodal tumor volumes (GTV_P & GTV_N), clinical target volume (CTV), and planning target volume (PTV).Six board-certified thoracic radiation oncologists were designated as the 'Experts' for this study. Their delineations were used to create a simultaneous truth and performance level estimation (STAPLE) contours using ADMIRE software (Elekta AB, Sweden 2017). Individual participants' contours were then compared with Experts' STAPLE contours.

Results: When compared to the Experts' STAPLE, GTV_P had the best agreement among all participants, while GTV_N showed the lowest agreement among all participants. There were no statistically significant differences in all studied parameters for all TVs for cases with 4D-CT versus cases with 3D-CT simulation scans.

Conclusions: High degree of inter-observer variation was noted for all target volume except for GTV_P, unveiling potentials for protocol modification for subsequent clinically meaningful improvement in target definition. Various similarity indices exist that can be used to guide multi-institutional radiotherapy delineation QA credentialing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ctro.2019.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365802PMC
February 2019

Optimisation of adaptive therapy for advanced Hodgkin lymphoma.

Lancet Oncol 2019 02 15;20(2):167-168. Epub 2019 Jan 15.

Imaging and Radiation Oncology Core, Lincoln, RI, USA; Department of Radiation Oncology, University of Massachusetts Medical School, Worcester, MA 01655, USA. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(19)30005-1DOI Listing
February 2019

Older adults fail to form stable task representations during model-based reversal inference.

Neurobiol Aging 2019 02 13;74:90-100. Epub 2018 Oct 13.

The Wellcome Trust Centre for Neuroimaging, University College London, London, UK; Max Planck-UCL Centre for Computational Psychiatry and Ageing Research, London, UK.

Older adults struggle in dealing with changeable and uncertain environments across several cognitive domains. This has been attributed to difficulties in forming adequate task representations that help navigate uncertain environments. Here, we investigate how, in older adults, inadequate task representations impact on model-based reversal learning. We combined computational modeling and pupillometry during a novel model-based reversal learning task, which allowed us to isolate the relevance of task representations at feedback evaluation. We find that older adults overestimate the changeability of task states and consequently are less able to converge on unequivocal task representations through learning. Pupillometric measures and behavioral data show that these unreliable task representations in older adults manifest as a reduced ability to focus on feedback that is relevant for updating task representations, and as a reduced metacognitive awareness in the accuracy of their actions. Instead, the data suggested older adults' choice behavior was more consistent with a guidance by uninformative feedback properties such as outcome valence. Our study highlights that an inability to form adequate task representations may be a crucial factor underlying older adults' impaired model-based inference.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neurobiolaging.2018.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338680PMC
February 2019

Specifying a Causal Role for Angular Gyrus in Autobiographical Memory.

J Neurosci 2018 12 24;38(49):10438-10443. Epub 2018 Oct 24.

Department of Psychology, University of Cambridge, Cambridge, United Kingdom CB2 3EB,

Considerable recent evidence indicates that angular gyrus dysfunction in humans does not result in amnesia, but does impair a number of aspects of episodic memory. Patients with parietal lobe lesions have been reported to exhibit a deficit when freely recalling autobiographical events from their pasts, but can remember details of the events when recall is cued by specific questions. In apparent contradiction, inhibitory brain stimulation targeting angular gyrus in healthy volunteers has been found to have no effect on free recall or cued recall of word pairs. The present study sought to resolve this inconsistency by testing free and cued recall of both autobiographical memories and word-pair memories in the same healthy male and female human participants following continuous theta burst stimulation (cTBS) of angular gyrus and a vertex control location. Angular gyrus cTBS resulted in a selective reduction in the free recall, but not cued recall, of autobiographical memories, whereas free and cued recall of word-pair memories were unaffected. Additionally, participants reported fewer autobiographical episodes as being experienced from a first-person perspective following angular gyrus cTBS. The findings add to a growing body of evidence that a function of angular gyrus within the network of brain regions responsible for episodic recollection is to integrate memory features within an egocentric framework into the kind of first-person perspective representation that enables the subjective experience of remembering events from our personal pasts. In seeking to understand the role played by the angular gyrus region of parietal cortex in human memory, interpreting the often conflicting findings from neuroimaging and neuropsychology studies has been hampered by differences in anatomical specificity and localization between methods. In the present study, we address these limitations using continuous theta burst stimulation in healthy volunteers to disrupt function of angular gyrus and a vertex control region. With this method, we adjudicate between two competing theories of parietal lobe function, finding evidence that is inconsistent with an attentional role for angular gyrus in memory, supporting instead an account in terms of integrating memory features within an egocentric framework into a first-person perspective representation that enables the subjective experience of remembering.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/JNEUROSCI.1239-18.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284111PMC
December 2018

The Importance of Imaging in Radiation Oncology for National Clinical Trials Network Protocols.

Int J Radiat Oncol Biol Phys 2018 11 18;102(4):775-782. Epub 2018 Oct 18.

Imaging and Radiation Oncology Core QA Center Rhode Island, University of Massachusetts Medical School, Lincoln, Rhode Island.

Imaging is essential in successfully executing radiation therapy (RT) in oncology clinical trials. As technically sophisticated diagnostic imaging and RT were incorporated into trials, quality assurance in the National Clinical Trials Network groups entered a new era promoting image acquisition and review. Most trials involving RT require pre- and post-therapy imaging for target validation and outcome assessment. The increasing real-time (before and during therapy) imaging and RT object reviews are to ensure compliance with trial objectives. Objects easily transmit digitally for review from anywhere in the world. Physician interpretation of imaging and image application to RT treatment plans is essential for optimal trial execution. Imaging and RT data sets are used to credential RT sites to confirm investigator and institutional ability to meet trial target volume delineation and delivery requirements. Real-time imaging and RT object reviews can be performed multiple times during a trial to assess response to therapy and application of RT objects. This process has matured into an effective data management mechanism. When necessary, site and study investigators review objects together through web media technologies to ensure the patient is enrolled on the appropriate trial and the intended RT is planned and executed in a trial-compliant manner. Real-time imaging review makes sure: (1) the patient is entered and eligible for the trial, (2) the patient meets trial-specific adaptive therapy requirements, if applicable, and (3) the intended RT is according to trial guidelines. This review ensures the study population is uniform and the results are believable and can be applied to clinical practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijrobp.2018.08.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6510266PMC
November 2018

The Influence of Imaging in the Modern Practice of Radiation Oncology.

Int J Radiat Oncol Biol Phys 2018 11 18;102(4):680-682. Epub 2018 Oct 18.

Imaging and Radiation Oncology Core (IROC) Rhode Island/University of Massachusetts Medical School, Worcester, Massachusetts.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijrobp.2018.08.028DOI Listing
November 2018

Dopaminergic basis for signaling belief updates, but not surprise, and the link to paranoia.

Proc Natl Acad Sci U S A 2018 10 8;115(43):E10167-E10176. Epub 2018 Oct 8.

Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, United Kingdom;

Distinguishing between meaningful and meaningless sensory information is fundamental to forming accurate representations of the world. Dopamine is thought to play a central role in processing the meaningful information content of observations, which motivates an agent to update their beliefs about the environment. However, direct evidence for dopamine's role in human belief updating is lacking. We addressed this question in healthy volunteers who performed a model-based fMRI task designed to separate the neural processing of meaningful and meaningless sensory information. We modeled participant behavior using a normative Bayesian observer model and used the magnitude of the model-derived belief update following an observation to quantify its meaningful information content. We also acquired PET imaging measures of dopamine function in the same subjects. We show that the magnitude of belief updates about task structure (meaningful information), but not pure sensory surprise (meaningless information), are encoded in midbrain and ventral striatum activity. Using PET we show that the neural encoding of meaningful information is negatively related to dopamine-2/3 receptor availability in the midbrain and dexamphetamine-induced dopamine release capacity in the striatum. Trial-by-trial analysis of task performance indicated that subclinical paranoid ideation is negatively related to behavioral sensitivity to observations carrying meaningful information about the task structure. The findings provide direct evidence implicating dopamine in model-based belief updating in humans and have implications for understating the pathophysiology of psychotic disorders where dopamine function is disrupted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1809298115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205436PMC
October 2018

αβ Integrin Mediates Radioresistance of Prostate Cancer Cells through Regulation of Survivin.

Mol Cancer Res 2019 02 28;17(2):398-408. Epub 2018 Sep 28.

Department of Radiation Oncology, University of Massachusetts Medical School, Worcester, Massachusetts.

The αβ integrin is involved in various physiologic and pathologic processes such as wound healing, angiogenesis, tumor growth, and metastasis. The impact of αβ integrin on the radiosensitivity of prostate cancer cells and the molecular mechanism controlling cell survival in response to ionizing radiation (IR) was investigated. Both LNCaP cells stably transfected with αβ integrin and PC-3 cells that contain endogenous β integrin were used. This study demonstrated that αβ integrin increases survival of αβ-LNCaP cells upon IR while small hairpin RNA (shRNA)-mediated knockdown of αβ integrin in PC-3 cells sensitizes to radiation. Expression of αβ integrin in LNCaP cells also enhances anchorage-independent cell growth while knockdown of αβ integrin in PC-3 cells inhibits anchorage-independent cell growth. The αβ antagonist, cRGD, significantly increases radiosensitivity in both αβ-LNCaP and PC-3 cells. Moreover, αβ integrin prevents radiation-induced downregulation of survivin. Inhibition of survivin expression by siRNA or shRNA enhances IR-induced inhibition of anchorage-independent cell growth. Overexpression of wild-type survivin in PC-3 cells treated with αβ integrin shRNA increases survival of cells upon IR. These findings reveal that αβ integrin promotes radioresistance and regulates survivin levels in response to IR. IMPLICATIONS: Future translational research on targeting αβ integrin and survivin may reveal novel approaches as an adjunct to radiotherapy for patients with prostate cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1541-7786.MCR-18-0544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359981PMC
February 2019

Preoperative Intensity Modulated Radiation Therapy Compared to Three-Dimensional Conformal Radiation Therapy for High-Grade Extremity Sarcomas in Children: Analysis of the Children's Oncology Group Study ARST0332.

Int J Radiat Oncol Biol Phys 2019 01 10;103(1):38-44. Epub 2018 Sep 10.

Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address:

Purpose: For pediatric patients with large, high-grade, extremity nonrhabdomyosarcoma soft-tissue sarcomas, preoperative radiation therapy (RT) provides the opportunity for smaller radiation fields and tumor shrinkage resulting in less extensive surgery. The potential disadvantage is an increased risk of wound complications after surgery compared with rates after postoperative chemoradiation. We assessed the impact of preoperative RT technique on target coverage in relationship to dose to skin and adjacent joints to determine whether acute wound complications and late musculoskeletal injury might be influenced by treatment technique.

Methods And Materials: Of 550 eligible patients <30 years of age, 200 were enrolled in arm D of ARST0332 and received neoadjuvant ifosfamide/doxorubicin, then chemoradiotherapy (45 Gy and ifosfamide) and surgery followed by postoperative RT if gross or microscopic positive surgical margins. One-hundred thirteen patients had extremity nonrhabdomyosarcoma soft-tissue sarcomas, of which 56 patients had preoperative RT plans for digital review. The doses to the target volume, skin (surface to 5 mm depth), adjacent joint, and extremity diameter were analyzed with respect to RT technique.

Results: Thirty-eight patients (65%) received 3-dimensional conformal RT (3D-CRT) and 18 (32%) received intensity modulated RT (IMRT). There was no difference in clinical target volume (CTV) size between groups (P = .920); however, IMRT plans had improved CTV coverage to 100% of the prescription dose compared with 3D-CRT plans (median CTV coverage, 92.7% vs 98.6%; P = .011). In patients without target overlap with the skin, IMRT use was associated with reduced percent volume of skin receiving 45 Gy or more (V45Gy) compared with 3D-CRT (median, 1.6% vs 6.3%, respectively; P = .005). IMRT was also associated with reduced V45Gy to the adjacent joint compared with 3D-CRT (median, 1.1% vs 13.2%; P = .018).

Conclusions: Preoperative IMRT may improve CTV coverage and reduce the volume of skin and adjacent joint treated to high doses. Future studies should assess whether these dosimetric findings produce differences in clinical and toxicity outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijrobp.2018.09.005DOI Listing
January 2019

Cardiac-Sparing Whole Lung IMRT in Patients With Pediatric Tumors and Lung Metastasis: Final Report of a Prospective Multicenter Clinical Trial.

Int J Radiat Oncol Biol Phys 2019 01 29;103(1):28-37. Epub 2018 Aug 29.

Imaging and Radiation Oncology Core, Providence, Rhode Island.

Purpose: A prospective clinical trial was conducted for patients undergoing cardiac sparing (CS) whole lung irradiation (WLI) using intensity modulated radiation therapy (IMRT). The 3 trial aims were (1) to demonstrate the feasibility of CS IMRT with real-time central quality control; (2) to determine the dosimetric advantages of WLI using IMRT compared with standard anteroposterior (AP) techniques; and (3) to determine acute tolerance and short-term efficacy after a protocol-mandated minimum 2-year follow-up for all patients.

Methods And Materials: All patients underwent a 3-dimensional chest computed tomography scan and a contrast-enhanced 4-dimensional (4D) gated chest computed tomography scan using a standard gating device. The clinical target volume was the entire bilateral 3-dimensional lung volume, and the internal target volume was the 4D minimum intensity projection of both lungs. The internal target volume was expanded by 1 cm to get the planning target volume. All target volumes, cardiac contours, and treatment plans were centrally reviewed before treatment. The different cardiac volumes receiving percentages of prescribed radiation therapy (RT) doses on AP and IMRT WLI plans were estimated and compared.

Results: The target 20 patients were accrued in 2 years. Median RT dose was 15 Gy. Real-time central quality assurance review and plan preapproval were obtained for all patients. WLI using IMRT was feasible in all patients. Compared with standard AP WLI, CS IMRT resulted in a statistically significant reduction in radiation doses to the whole heart, atria, ventricles, and coronaries. One child developed cardiac dysfunction and pulmonary restrictive disease 5.5 years after CS IMRT (15 Gy) and doxorubicin (375 mg/m). The 2- and 3-year lung metastasis progression-free survival was 65% and 52%, respectively.

Conclusions: We have demonstrated the feasibility of WLI using CS IMRT and confirmed the previously reported advantages of IMRT, including superior cardiac protection and superior dose coverage of 4D lung volumes. Further studies are required to establish the efficacy and safety of this irradiation technique.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijrobp.2018.08.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391051PMC
January 2019
-->